Abstract

The maternal-fetal disposition of labetalol, a combined alpha-1 and beta adrenergic blocker, and its pharmacodynamics in pregnancy are not well understood. This study describes the pharmacokinetics, cardiovascular and metabolic effects of labetalol in the mother and in utero fetus after a 100-mg maternal i.v. bolus administration, in the chronically instrumented pregnant sheep. Labetalol shows a triexponential decline in the mother with a total body clearance of 30.8 +/- 3.83 ml/min/kg, an apparent steady-state volume of distribution (nonparametric) of 3.02 +/- 0.18 liters/kg and terminal elimination half-life of 2.79 +/- 0.66 hr. These estimates are similar to the reported values in pregnant women. Labetalol rapidly crosses the sheep placenta. The peak fetal plasma concentration was 33.7 +/- 5.8 ng/ml, the fetal exposure to labetalol as calculated by the fetal to maternal area under the curve ratio was 14.37 +/- 1.54% and the apparent fetal elimination half-life was 3.71 +/- 0.5 hr. Labetalol persists in the amniotic and fetal tracheal fluids up to 24 hr with concentrations reaching 2- to 4 times the fetal plasma concentration. Whereas there were no significant maternal or fetal cardiovascular effects, some very significant metabolic effects were observed, including fetal and maternal lactic acidosis and hyperglycemia. Lactic acid accumulates in the fetal blood and amniotic fluid with peak concentrations (6.0 +/- 0.31 and 5.5 +/- 0.26 mM, respectively) showing a more than 300% increase over control values. The exact mechanism by which labetalol causes these metabolic effects is not clear, but it may involve its partial beta-2 agonist activity.